Bioabsorbable surgical devices made from bioabsorbable polymers are becoming more frequently used in the medical profession in bone-to-bone, soft tissue-to-bone or soft tissue-to-soft tissue fixation. Numerous publications describe bioabsorbable devices for tissue fixation applications. (See e.g. U.S. Pat. Nos. 4,655,203; 4,743,257; 4,863,472; 5,084,051; 4,968,317; EPO Pat. No. 449,867; U.S. Pat. No. 5,562,704; PCT/FI 96/00351; PCT/FI 96/00511; FI Pat. Appl. No. 965111; U.S. patent application Ser. No. 08/873,174; U.S. patent application Ser. No. 08/887,130; U.S. patent application Ser. No. 08/914,137; and U.S. patent application Ser. No. 08/921,533.
In the case of bioabsorbable tissue fixation devices, surgeons would prefer to use such devices that eventually resorb and disappear from the body after their function during tissue fixation and healing has been served. Such a device made from a bioabsorbable polymer must have sufficient strength and stiffness for effective tissue fixation and must retain sufficient strength to perform its function during the tissue healing process before being absorbed by the body.
It is advantageous to mix different additives, like drugs, into bioabsorbable polymers to modify their properties and/or to achieve useful properties. Antibiotics are typical additives, which can promote clinical performance of the surgical device and can be released from the device in vivo to counter an infection and/or prevent the colonization of bacteria on the surface of the device.
A well-known procedure for treatment of bone infections is the use of polymethymethacrylate (PMMA) beads that contain antibiotics (e.g. SEPTOBAL® beads). Such beads are placed in surgical voids and thereby fill the voids, as well as provide local bactericidal levels of antibiotic. However, even these PMMA beads have disadvantages. First, they usually can only provide bactericidal levels of antibiotic for about a few weeks, so parenteral antibiotic must also be administered. Second, the PMMA beads must eventually be removed surgically, resulting in further trauma to the patient's body. Third, PMMA beads do not facilitate new bone formation in any way. Additionally, PMMA bends act as fillers and they have no effect as a bone fracture fixation device. Antibiotics may also be mixed with a PMMA bone cement, which, however, is a non-absorbable biomaterial.
A long-standing need exists for improved methods of preventing and treating infections in fixation of bone fractures and osteotomies. An especially long-standing need exists for strong, totally synthetic, bioabsorbable drug-releasing implants for preventing and/or treating infections in fixation of bone fractures and osteotomies, which implants give a secure fixation of bone fracture and prevent and/or treat infections by starting rapid continuous antibiotic release in therapeutic concentrations and also by releasing antibiotics over several weeks or months.
The principles of synthetic, bioabsorbable polymeric fracture fixation devices, which can contain and release antibiotics, were described for the first time in the late 1980s. For example, U.S. Pat. No. 4,610,692 describes a method of producing sintered tricalcium phosphate implants for filling bone cavities and for fixing bone fragments in a living body, which comprises: mixing tricalcium phosphate with at least one substance which under heat sufficiently high to bake said tricalcium phosphate forms a gas; shaping the thus-formed mixture into shaped bodies thereof; baking the shaped bodies at a temperature sufficiently high to cause gas formation from said substance, thereby forming pores in said shaped bodies; impregnating said shaped porous bodies with a therapeutically-active ingredient, thereby distributing the same in the pores; and coating at least a part of one of said shaped, porous bodies having said therapeutically-active ingredient distributed therein, with a coating of a predetermined thickness of a biodegradable substance, whereby the time of absorption of said therepeutically-active ingredient is controlled by the thickness of said biodegradable substance. Sintered ceramic bodies, however, are brittle and mechanically weak, which is a risk factor when such materials are used in manufacturing of implants for fixing of bone fragments. Additionally, the biodegradable coating on the porous body may prevent bone growth into the pores of the tricalcium phosphate body as long as the coating is uniform. Therefore, there is not an advantageous synergism of release of antibiotic and growth of bone tissue into contact with absorbing ceramic filler phase. Also, the therapeutically-active ingredient is not mixed with a bioabsorbable matrix in this case, but is distributed among the pores within the tricalcium phosphate body.
PCT/FI 88/00108 and PCT/FI 90/00113 describe absorbable, self-reinforced polymeric materials and absorbable fixation devices for different surgical purposes for fixation of different tissues or parts of tissues by internal or external fixation techniques. These references describe that materials of the invention can contain different additives, like antibiotics, which can give the materials special functional advantages. However, no information is given of antibiotic release from such materials and implants.
U.S. Pat. No. 4,347,234 describes a collagen based drug delivery system which is resorbable in the body. Even if this drug delivery system can be used in the treatment of osteomyelitis, it contains a substantial amount of animal or human-based collagen. Biological tissue-based biomaterials have aroused concern because of the risk of delivering host based diseases, like viral or prion infections, into the human patients (See e.g. S. Yamada et al. Neurosurgery, 34 (4) 1994, p. 740-743). It is well known that collagen based materials became flexible in tissue conditions because of water absorption. Therefore, they cannot be applied as fracture fixation materials. Therefore, a totally synthetic drug-delivery system should be preferable.
Bioabsorbable polymeric drug delivery systems for the treatment of chronic osteomyelitis were described further in 1991-1992 by several groups. C. Teupe et al., in “Ciprofloxacin-impregnated poly-L-lactic acid drug carrier”, Arch. Orthop. Trauma Surg. 112 (1992) 33-35 and S. Winckler et al., in “Resorbierbare Antibiotikumträger zur lokalen Behandlung der chronischen Osteitis—Polyglykolsäure/Poly-L-Laktid als Träger, Experimentelle Untersuchungen in vitro”, Langenbecks Arch. Chir. 377 (1992) 112-117, described bioabsorbable polyglycolic acid (PGA) and poly-L-lactic (PLLA) cylinders containing antibiotic ciprofloxacin which is released from cylinders in hydrolytic and in vivo conditions during several weeks in therapeutic doses. No information is given of long lasting, therapeutic level release of antibiotics from these implants, which were manufactured from antibiotic impregnated fibers with a slow and complicated sintering process.
U.S. Pat. No. 5,268,178 describes bioabsorbable antibiotic implants comprising at least one antibiotic drug. U.S. Pat. No. 5,281,419 describes an antibiotic impregnated fracture fixation device and antibiotic impregnated drug delivery polymer. However, no indication of therapeutic release level of antibiotics of these implants is given in either reference.
Di Silvio and Bonfield describe a drug delivery system comprising gelatin for the combined release of therapeutic levels of both gentamicin and growth hormone in “Biodegradable drug delivery system for the treatment of bone infection and repair,” Int. Conf. Adv. Biomater. and Tissue Eng., June 14-19, Capri, Italy, Book of Abstracts, 1998, p. 89-90. Even if this system combines a sustained release of antibiotics in combination with a bone stimulating factor, this system releases gentamicin only up to 14 days. This is in many cases too short of an influence time of an antibiotic. Effective healing of an osteomyelitis may need antibiotic(s) treatment of at least several weeks (see e.g. L. Dahl et al., Scand. J. Infect. Dis., 30 (6), (1998) p. 573-7 or S. Veng et al., J. Trauma, 46 (1) (1999) p. 97-103). Additionally, gelatin based systems are mechanically weak and cannot be used in the form of bone fracture fixation implants. Also, as mentioned above, animal based biomaterials, like gelatin, have aroused concern of the risk of delivering animal based diseases, like viral infections, into human patients. Further, the release of a bone growth promoting factor from the drug delivery system was limited to 2 weeks, which is far too short time for proper new bone formation, which in the case of cancellous bone is at least 6 weeks.
Accordingly, there is need for a method of enhancing drug release from a synthetic, bioabsorbable product, which has tissue supporting function, high mechanical strength and releases drug in therapeutic doses over several weeks or months.